Trastuzumab Deruxtecan Meets ORR End Point in HER2-expressing Advanced Solid Tumors

The antibody-drug conjugate trastuzumab deruxtecan met the prespecified target for objective response rate and demonstrated durable responses in heavily pretreated patients with HER2-expressing advanced solid tumors in the phase 2 DESTINY-PanTumor02 trial.

The antibody-drug conjugate (ADC) fam-trastuzumab deruxtecan-nxki (Enhertu) met the prespecified target for objective response rate (ORR) and demonstrated durable responses in heavily pretreated patients with HER2-expressing advanced solid tumors in the phase 2 DESTINY-PanTumor02 trial (NCT04482309).1

The trial included previously treated patients with locally advanced, unresectable, or metastatic solid tumors, such as biliary tract, bladder, cervical, endometrial, ovarian, pancreatic, and rare cancers, who were not eligible for curative therapy.

Detailed findings from the study will be presented at an upcoming medical meeting.

“The clinically meaningful responses seen in the DESTINY-PanTumor02 trial reaffirm our belief in the potential of [trastuzumab deruxtecan] across multiple HER2-expressing cancers,” Ken Takeshita, global head of Research and Development at Daiichi Sankyo, stated in a news release. “The results seen so far across multiple cohorts of the trial will inform next steps of our broad development program as we look to bring this important medicine to as many patients as quickly as possible.”

In May 2022, the FDA granted regular approval to trastuzumab deruxtecan for adult patients with unresectable or metastatic HER2-positive breast cancer who have previously received an anti–HER2-based regimen either in the metastatic setting, or in the neoadjuvant or adjuvant setting, and have developed disease recurrence during or within 6 months of therapy completion.2 Additionally, in August 2022, the regulatory agency approved the ADC for the treatment of patients with unresectable or metastatic HER2-low breast cancer.3

Later in August 2022, the FDA granted an accelerated approval to trastuzumab deruxtecan for adult patients with unresectable or metastatic non–small cell lung cancer whose tumors have activating HER2 mutations, as detected by an FDA-approved test, and who have received previous systemic therapy.4 In January 2021, the regulatory agency approved the ADC for the treatment of adult patients with locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma who have received a previous trastuzumab (Herceptin)-based regimen.5

“[Trastuzumab deruxtecan] has already demonstrated its potential to improve outcomes for patients with HER2-targetable breast, gastric and lung cancers, and these positive initial results in other tumor settings with significant unmet need are very encouraging,” Cristian Massacesi, chief medical officer and oncology chief development officer at AstraZeneca, stated in a news release.1 “The DESTINY-PanTumor02 results mark an important step forward in our understanding of the potential role of [trastuzumab deruxtecan] across multiple HER2-expressing tumor types.”

The global, multicenter, multi-cohort, open-label phase 2 DESTINY-PanTumor02 trial has enrolled 268 patients with locally advanced, unresectable or metastatic solid tumors who progressed following prior treatment or who have no satisfactory alternative treatment option.6 Prior HER2-targeted therapy was permitted, and HER2 expression for eligibility was based on local or central assessment. Patients were also required to have measurable target disease assessed by the investigator per RECIST v1.1 criteria, and have protocol-defined adequate organ function, including cardiac, renal, and hepatic function.

The trial excluded patients with a history of non-infectious pneumonitis/interstitial lung disease (ILD) that required steroids, current ILD, or where suspected ILD that could not be ruled out by imaging at screening. Lung-specific intercurrent clinically significant severe illnesses were not permitted.

Patients in all cohorts received 5.4 mg/kg of intravenous trastuzumab deruxtecan every 3 weeks. Investigator-assessed confirmed ORR served as the trial’s primary end point, and secondary end points included duration of response, disease control rate, progression-free survival, overall survival, safety, tolerability, and pharmacokinetics.1

The safety profile of trastuzumab deruxtecan observed in patients treated during DESTINY-PanTumor02 was consistent with previously reported trials of the ADC, and no new safety signals were identified.​

References

  1. Enhertu showed clinically meaningful and durable responses across multiple HER2-expressing tumour types in DESTINY-PanTumor02 phase II trial. News release. AstraZeneca. March 6, 2023. Accessed March 6, 2023. https://www.astrazeneca.com/media-centre/press-releases/
  2. FDA grants regular approval to fam-trastuzumab deruxtecan-nxki for breast cancer. News release. FDA. May 4, 2022. Accessed March 6, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/
  3. FDA approves first targeted therapy for HER2-low breast cancer. News release. FDA. August 5, 2022. Accessed March 6, 2023. https://www.fda.gov/news-events/press-announcements/
  4. FDA grants accelerated approval to fam-trastuzumab deruxtecan-nxki for HER2-mutant non-small cell lung cancer. News release. FDA. August 11, 2022. Accessed March 6, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/
  5. FDA approves fam-trastuzumab deruxtecan-nxki for HER2-positive gastric adenocarcinomas. News release. FDA. January 15, 2021. Accessed March 6, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/
  6. A phase 2 study of T-DXd in patients with selected HER2 expressing tumors (DPT02). ClinicalTrials.gov. Updated February 23, 2023. Accessed March 6, 2023. https://clinicaltrials.gov/ct2/show/NCT04482309